Chronic intestinal inflammatory diseases are a heterogeneous group of pathologies characterised by alternating phases of activity and remission. These are diseases of an inflammatory nature, with acute or insidious onset, which mainly, but not exclusively affect the intestine, with chronic course and fluctuating activity and progression over time.
These diseases represent an issue of growing importance, also because their incidence and prevalence are increasing either due to the environmental factors typical of industrialised society, or because of the greater diagnostic capability of health professionals.
In this group of diseases, the most significant ones are ulcerative colitis and Crohn's disease, both serious and disabling diseases, which have a negative impact upon the quality of life of patients as well as on their state of health.
Ulcerative colitis is an inflammatory disease of the colon that mainly involves ulceration and bleeding of the intestinal mucosa, severe abdominal pain and diarrhoea. It is a disease that usually has a chronic course, with acute exacerbation in symptoms (abdominal pain, diarrhoea, rectal bleeding, uncontrolled bowel movement, anaemia, weight loss, general poor health). Sometimes it comes with fulminating onset. The incidence of ulcerative colitis fluctuates between 3 and 20 new cases/100000 citizens per year. The most susceptible age group is that between 20 and 40 years old. The complications of the disease include stenosis or intestinal perforation, massive haemorrhage, toxic megacolon, cancer. The complications are responsible for death within a year of the onset of the disease in 4-6% of patients over 60 years old. Crohn's disease is a chronic inflammatory disease that can be located in any part of the orodigestive tract. The age of onset is typically between 15 and 40 years, but it can also occur in infants. In Italy the incidence is 4-5 cases/100000 citizens per year (much higher in Northern Europe and USA), with a prevalence of about 52 cases/100000 citizens. The most frequently affected tract is the terminal ileum and the first tract of the colon. The inflammatory process affects the entire intestinal wall, and it can also cause complications to the adjacent organs. It can be associated with auto-immune phenomena, for example affecting the skin, the eyes and the joints. The most common local complication is represented by intestinal blockage; in various cases, surgical resection of an intestinal tract is necessary. Overall, the disease has a mortality that is roughly double that of the general population.
Corticosteroids or cortisones represent a very important class of drugs used in the therapy of intestinal chronic inflammatory diseases. They are analogous to hormonal substances produced physiologically in the adrenal gland and they are characterised by high anti-inflammation activity.
Glucocorticoids, belonging to the class of corticosteroids, suppress the inflammation through the reduction of the inflammatory exudate, the reduction of the production of inflammatory mediators, the reduction of recruitment of inflammatory cells at the point of inflammation and the reduced activation of inflammatory cells.
Their therapeutic efficacy in inflammatory intestinal diseases has been recognised for about 50 years and, since then, their use has greatly changed the natural history of diseases, which before were diseases dealt with mainly surgically.
Conventional corticosteroids are used exclusively in the moderate-severe forms of disease (for example using high doses of prednisone delivered parenterally).
It is also possible to use cortisones delivered topically, associated with mesalazine enemas, which can for example be particularly effective in the distal forms of ulcerative colitis. However, it should be remembered that the cortisones used systemically, as well as these benefits also involve, particularly if used for repeated cycles, a series of important adverse effects due greatly to their action on the hypophysis-cortico-adrenal system (for example diabetes, osteoporosis, hypertension, cataracts, hirsutism, mental disorders, etc.). Moreover, cortisones administered rectally, whilst having less side effects, do not allow the proximal tracts of the colon to be reached.
Beclomethasone dipropionate (BDP) is a cortisone 500 times more powerful than hydrocortisone, with low water solubility, inactive at the hepatic level, equipped with high receptor affinity, with low intestinal absorption and absence of inhibition of the hypophysis-cortico-adrenal system.
It is currently used in the treatment of ulcerative colitis both delivered orally, in the form of slow-release tablets, and as a liquid enema or rectal foam.
In general, currently, in the treatment of pathologies of the descending colon or of the rectum, there is preferably local application of the active ingredient, through clysters or enemas, to avoid the absorption of the active ingredient during the gastrointestinal journey before it reaches the colon or rectum. Consequently, the release of pharmacologically active agents at the level of the colon or rectum can only be obtained by rectal administration through, for example, foams, liquid enemas, gels or suppositories, associated with a suitable formulation taken orally that, in most cases, experiences better compliance of the patient with respect to rectal administration.
The only pharmaceutical compositions for oral use containing BDP currently on the market (Clipper®) are formulated in slow release tablets.
Patent application US2006/0210631 describes modified-release pharmaceutical compositions for the oral administration of an active ingredient to the colon in which said active ingredient is part of a core.
The fact that the active ingredient is inserted inside a core, like in the formulations of the prior art, can lead to non-homogeneous release thereof and can even not guarantee its complete release.
There is therefore the need for solid oral compositions that ensure higher standards in terms of release, as well as of distribution and homogeneity of content of the active ingredient itself with respect to the compositions of the prior art.